We propose to examine whether changes in sleep alter pain and pain-related outcomes in adults with Sickle Cell Disease (SCD). Adults living with SCD report acute, painful vaso-occlusive crises and chronic pain that contribute to disability, often require chronic reliance on opioid therapy, and increase health care utilization. As many as 70% of adults with SCD experience various sleep disturbances. Pain and sleep are inter-related, such that pain disturbs sleep and disturbed sleep amplifies pain and increases risk for developing chronic pain. Thus, we propose to test whether disrupted sleep increases, and improved sleep decreases, pain and pain- related outcomes in SCD. Pain processing occurs in the central nervous system, where nociceptive input can be inhibited or facilitated and which can undergo both functional and structural plasticity. When plasticity results in amplification of pain, this central sensitization (CS) manifests as hyperalgesia, allodynia, and spreading of pain and is an important treatment target in its own right. A growing literature implicates central sensitization in SCD, and we find a strong association between laboratory-evoked CS and sleep disturbance in SCD. The neural substrates involved in pain modulation are often disrupted in chronic pain, likely due to the demands pain places on cognitive resources, and similar effects are seen with chronic insomnia. It remains unclear whether these changes occur in SCD and if improving sleep improves central modulation of pain. The potential for improved sleep to reduce pain and CS requires additional investigation, particularly given the significance of sleep disturbance as a mutable risk factor. We will conduct two studies; one will experimentally disrupt sleep and one will clinically improve sleep. Pain outcomes for both studies include clinical pain, laboratory measures of CS, and functional connectivity of cognitive and pain modulatory networks; the second study includes crises and healthcare utilization as secondary outcomes. Our aims are the following: 1) to determine whether experimentally disturbed sleep alters CS and clinical pain in SCD; 2) to determine the extent to which experimentally disturbed sleep alters functional connectivity of cognitive and pain modulatory networks using brain imaging; 3) to determine whether treatment of sleep improves pain outcomes in SCD; and 4) to determine whether treatment of sleep alters functional connectivity of cognitive and pain modulatory networks using brain imaging in SCD. Understanding the contribution of sleep disturbance to increased pain sensitivity will enhance our knowledge of pain in sickle cell disease as well as other chronically painful conditions. Since treatment options are limited for individuals living with SCD, cognitive behavioral treatment of insomnia may provide an effective, non-pharmaceutical approach to improving multiple pain-related outcomes.